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1
Yao, Ya-Li. "Regulation of yy1, a multifunctional transciption [sic] factor /". [Tampa, Fla.] : University of South Florida, 2001. http://purl.fcla.edu/fcla/etd/SFE0000626.
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2
Zandvakili, Arya. "The Role of Affinity and Arrangement of Transcription Factor Binding Sites in Determining Hox-regulated Gene Expression Patterns". University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535708748728472.
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Elzi, David John. "Transcriptional properties of the Kaiso class of transcription factors /". Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/5027.
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4
Bidon, Baptiste. "Mediator and NER factors in transcription initiation". Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ093/document.
Testo completoAbstract (sommario):
La synthèse d’ARN messagers résulte d’une cascade d’évènements temporellement et spatialement orchestrée. Au moment de l’initiation de la transcription, divers facteurs tels que les facteurs généraux de transcription, le complexe Médiateur, des co-activateurs, des facteurs de remodelage de la chromatine ainsi que l’ARN polymérase II sont recrutés au niveau de la région promotrice du gène. Certains facteurs de la voie NER de réparation de l’ADN sont également recrutés. En utilisant des cellules de patients porteurs de mutations dans les gènes MED12 (sous-unité du Médiateur) ou XPC (facteur initiant la voie NER), nous avons pu étudier le rôle de ces protéines dans la transcription. Les patients MED12 sont notamment caractérisés par une lourde déficience intellectuelle et des malformations congénitales. Nous avons montré que MED12 est impliqué dans le contrôle de certains gènes de réponse immédiate comme JUN, qui contribue notamment au développent et à la plasticité cérébrale. L’expression de ce dernier est affectée par les mutations de MED12, mais différemment en fonction de la position de la mutation, apportant une possible indication sur l’origine des variations phénotypiques observées chez les patients. En parallèle, les patients XPC se caractérisent par une forte photosensibilité. Nous avons montré que la protéine XPC, en collaboration avec le facteur E2F1, est impliquée dans le recrutement de l’histone acetyl-transférase GCN5 au niveau du promoteur d’un certain nombre de gènes. Cette dernière permet notamment l’a modification de l’environnement chromatinien, en coopération avec le facteur général de transcription TFIIH et participe ainsi à l’initiation de la transcription. En plus d’approfondir la compréhension des mécanismes régissant la transcription, ces résultats ont permis de mieux comprendre l’étiologie des maladies associées aux mutationsThe synthesis of messenger RNA is a highly regulated process. During transcription initiation, a large number of proteins are recruited to gene promoter, including the RNA polymerase II, general transcription factors, co-activators, chromatin remodellers and the Mediator complex. Some DNA repair factors from the NER pathway are also recruited. Using cells derived from patients bearing mutations in either MED12 gene or XPC gene, we studied the roles of such proteins in transcription. MED12 patients are mostly characterised by intellectual disability and developmental delay. We showed that MED12 is implicated in the transcription regulation of immediate early genes like JUN, known for its role in neurological development and neuronal plasticity. JUN expression is markedly altered by MED12 mutations. We also showed that the position of the mutation influences this alteration, bringing possible explanation for inter-patients symptom variability. Meanwhile, XPC patients are mostly characterized by photosensitivity. We showed that XPC protein, which engages one of the NER pathways, is implicated in chromatin post-translational modification. Together with E2F1, it helps the recruitment of GCN5 acetyl-transferase to promoter of a certain set of genes. On the promoter, GCN5 notably cooperates with TFIIH to modify the chromatin environment during transcription initiation. In addition to help the comprehension of the transcription mechanisms, these results bring knew insight into the aetiology of mutations associated diseases
5
Brunkhorst, Adrian. "A study on the TFIID subunit TAF4 /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-206-3/.
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6
Dennis, Jonathan Hancock. "Transcriptional regulation by Brn 3 POU domain containing transcription factors". Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249684.
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7
Greberg, Maria Hellqvist. "Cloning and characterization of FREACs, human forkhead transcription factors". Göteborg : Dept. of Cell and Molecular Biology, Göteborg University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/39751934.html.
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8
Chanapai, Seni. "Photocontrol of artificial transcription factors". Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/58014/.
Testo completoAbstract (sommario):
The design of a photoswitchable homeodomain artificial transcription factor (PATF), modelled on an engrailed homeodomain, for the purpose of controlling DNA binding affinity and controlling the transcription process in cells using light has been investigated. This study was conducted using a 3,3’-bis(sulfo)- 4,4’bis(chloroacetamino)azobenzene crosslinker, alkylated between two cysteine residues with different spacings (i, i+4, i, i+7 and i, i+11) and either a rigid or flexible linker domain. In previous studies, basic leucine zipper transcription activators have been photocontrolled in living cells by incorporating a photoswitchable azobenzene crosslinker. Circular dichroism spectroscopy showed the conformation of crosslinked PATF (XLPATF) peptides (i, i+11 spacing) containing rigid and flexible linkers could be controlled reversibly by light. Fluorescence anisotropy experiments using labelled DNA confirmed the in vitro DNA binding affinity of PATF was considerably higher with the crosslinker in the trans (ground state) configuration than in the cis (photoexcited state) configuration. Further studies of peptides with i, i+4 and i, i+7 spacings with a semirigid and rigid linker domains showed increased binding affinity with the crosslinker in the cis configuration. Initiation of transcription was investigated by an in vitro transcription assay to measure the ability of PATF molecules to moderate the production of RNA by irradiation with UV light. PATF molecules with i, i+11 spacings showed increased transcriptional activation with the crosslinker in the ground state configuration and i, i+4 and i, i+7 spacings resulted in increased transcription activation with the crosslinker in the excited state conformation. Control of 50% of transcriptional activity was achieved for i, i+11 v spacings, and PATFs with a rigid linker domain were more effective switches than those with flexible linkers. Using i, i+4 and i, i+7 spacings in PATFs resulted in a lower degree of control but, as anticipated, transcriptional activation was increased after irradiation.
9
Mekala, Vijaya Krishna Wysocka-Diller Joanna. "Isolation and characterization of Scarecrow suppressor mutants in Arabidopsis thaliana". Auburn, Ala, 2008. http://repo.lib.auburn.edu/EtdRoot/2008/FALL/Biological_Sciences/Thesis/Mekala_Vijaya_18.pdf.
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10
Ching, Chi-yun Johannes, e 程子忻. "Transcriptional regulation of p16INK4a expression by the forkhead box transcription factor FOXM1". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B29466192.
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11
Pinacho, Garcia Raquel. "SP Transcription factors in psychotic disorders". Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/327025.
Testo completoAbstract (sommario):
Psychotic disorders including bipolar disorder and schizophrenia are a leading cause of disability across the world but the underlying pathophysiological mechanisms remain poorly understood. Available treatments are inadequate for some sets of symptoms as is the case for negative symptoms in schizophrenia. Alterations in brain connectivity, synaptic plasticity, N-methyl D aspartate receptor (NMDAR) signalling and calcium homeostasis have been suggested to contribute to these disorders. However, the particular transcriptional programmes altered in these disorders are not fully characterised. Previous data suggested that the transcription factors specificity protein 4 (SP4) and SP1 may be involved in the pathophysiology of psychotic disorders. We hypothesized that the expression and/or function of SP4 and SP1 may be altered in psychotic disorders through the regulation of transcriptional programmes involved in neuronal patterning, synaptic plasticity and glutamate signalling. In this doctoral Thesis we aimed to characterise the contribution of SP4 and SP1 transcription factors to the pathophysiology of psychotic disorders. By using real time quantitative RT-PCR and/or immunoblot techniques, we analysed the expression of SP factors, of SP4 S770 phosphorylation and/or of selected SP-regulated gene targets in at least one of the following substrates: (i) rat cerebellar granule neurons (CGNs), (ii) the postmortem brains of bipolar disorder, schizophrenia and control subjects, (iii) peripheral mononuclear blood cells (PMBC) of first-episode psychosis, and (iv) the rodent hippocampus after NMDAR blockade and antipsychotic treatment.
We found that membrane depolarisation regulates SP4 protein levels in CGNs by preventing SP4 degradation via the ubiquitin-proteasoma pathway and that lithium prevents SP4 degradation and increases SP1 gene expression in non-depolarising conditions. In postmortem human tissue, we found a reduction in protein but not mRNA expression of SP4 and SP1 in the cerebellum in subjects with bipolar disorder and in subjects with more severe negative symptoms in schizophrenia. We have also found reduced expression of protein and mRNA levels of SP4 in the prefrontal cortex in bipolar disorder and of SP1 in the same region in schizophrenia, suggesting a disorder-specific regulation in this area. In contrast, both SP4 and SP1 protein and mRNA levels were increased in the hippocampus in schizophrenia. Consistent with this, we also observed an increase of SP1 and SP4 protein levels in the hippocampus of a mouse model of psychosis, but not in the hippocampus of a rat model of chronic antipsychotic treatment, suggesting that this upregulation may be present from the early stages of psychosis.
We further characterised the phosphorylation of SP4 at serine 770 (S770), which is regulated by membrane depolarisation and NMDAR activity. We found an increase of SP4 S770 phosphorylation in conditions where SP4 protein levels are reduced, namely in the cerebellum of bipolar disorder and of schizophrenia patients with more severe negative symptoms, as well as in PMBC in first-episode psychotic patients. These results suggest that an imbalance in SP4 abundance may be regulated by NMDAR-dependent SP4 phosphorylation in the brain. Moreover, we found that reduced expression of NR2A and DRD2 in the cerebellum of schizophrenia patients correlated with more severe negative symptoms and SP protein levels. Additionally, we show here evidence for an imbalance in the SP4-NWK2-NR1 pathway in the cerebellum of patients with bipolar disorder. This pathway is involved in NR1 subunit availability on the cell surface, suggesting that SP4 could contribute to altered NR1 receptor trafficking in psychotic disorders.
Together, the results presented in this Thesis suggest an imbalance in SP4 and SP1 transcription factors in the brains of patients with bipolar disorder and schizophrenia that may contribute to alterations in NMDAR receptor signalling and thereby to the impaired synaptic plasticity and altered brain connectivity observed in psychotic disorders.
12
Müller, Susanne. "Transcription factors regulating the Btk promoter /". Stockholm, 1997. http://diss.kib.ki.se/1997/91-628-2717-0.
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13
Paik, Elizabeth Jae-Eun. "Caudal Transcription Factors in Hematopoietic Development". Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10254.
Testo completoAbstract (sommario):
During embryogenesis, hematopoietic cells arise from the lateral plate mesoderm (LPM) following gastrulation. The transcriptional program required for this LPM to blood switch is not fully understood. Previous work on a zebrafish mutant with a deletion in the cdx4 gene demonstrated the importance of this caudal transcription factor in the LPM to blood transition. To explain how cdx4 regulates embryonic hematopoiesis, two main approaches were taken in this thesis. The first part of the thesis describes a chemical genetics screen that identified cdx4 interacting pathways. To find small molecules that could rescue the loss of red blood cells caused by the cdx4 deletion, cdx4 mutant embryos were incubated with 2640 compounds from the beginning of the gastrula stage to the 10-somite stage. Two related psoralen compounds, Bergapten (Ber) and 8-methoxypsoralen (8-MOP), rescued the erythroid progenitors in the cdx4 mutants. This rescue is closely linked to the compounds' effects on anteriorposterior patterning, reminiscent of retinoic acid pathway compounds. The second part of my thesis identifies a Cdx4-Sall4 transcriptional module in the LPM. Chromatin-immunoprecipitation coupled to sequencing (ChIP-seq) and microarray analysis revealed that Cdx4 directly regulates cdx4 and a zinc finger transcription factor spalt-like 4 (sall4) transcription. Sall4 ChIP-seq showed that Sall4 also binds to its own locus and to the cdx4 locus, suggesting an auto- and cross-regulation between two transcription factors. In addition, Cdx4 and Sall4 bind to common genomic regions proximal to mesodermal progenitor (tbx16 and mespa) and hematopoietic genes (scl, gata2a, and ldb1a), indicating Cdx4 and Sall4 co-regulate key genes that are required for LPM and blood specification. sall4 knockdown in the cdx4 mutants demonstrated that Sall4 synergizes with Cdx4 in regulating embryonic hematopoiesis. These findings suggest that auto- and cross-regulation of Cdx4 and Sall4 establish a stable circuit in the LPM that facilitates the activation of blood-specific program as development proceeds. How undifferentiated germ layers transition into various tissues is a key question in developmental biology. My thesis establishes a model based on LPM to blood transition, which is also applicable to other studies on germ layer specification.
14
Costanzo, Federico. "Role of NER factors in transcription". Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAJ099.
Testo completoAbstract (sommario):
Les mutations dans les gènes codant pour les facteurs NER donnent lieu à des maladies autosomiques récessives telles que Xeroderma pigmentosum (XP), le syndrome de Cockayne (CS) et la trichothiodystrophie (TTD). Les phénotypes associés à ces syndromes génétiques se caractérisent par une sensibilité extrême à la lumière UV, avec prédisposition accrue à certains cancers (pour XP et XP / CS combiné, principalement), ainsi qu’un retard mental et des signes de progeria (pour CS et XP / CS combiné). Si on peut admettre une corrélation entre réparation de l'ADN endommagé et sensibilité aux UV / cancer, celle avec les symptômes neurologiques/progéroïdes est encore sujet à débat. Une explication pourrait provenir du rôle des facteurs NER dans la régulation de la transcription. Nous proposons une vue d’ensemble des roles de XPG et XPC dans la régulation de la transcription en absence des stress exogènes et comment CSA et CSB orchestrent l’arret de la transcription après une attaque génotoxique. XPC était capable d’interagir stablement avec la methyltransferase NSD3. Des mutations dans XPC altèrent le transcriptôme et la distribution des H3K36me3. Les mutations dans XPG dérégulent l’expression génique et XPG est capable d’etre recruté sur l’ensemble du genôme avec TFIIH. CSA et CSB faisant partie de la machinerie ubiquitin/proteasôme, régulent le recrutement de facteurs fixant l’ADN et contrôlant le programme transcriptionnel après irradiation aux UV. Nos donnés mettent en évidence le rôle des facteurs NER dans la transcription et leur défaut d’action provoque les maladies XP et XP/CS. En plus, nos données fournissent des explications sur le méchanisme d’arrêt de la transcription après un stress genotoxique et pose la question de l’origine du phenotype CSMutations in genes coding for NER factors give rise to autosomal recessive diseases such as Xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). The phenotypes associated with these genetic syndromes spans from extreme sensitivity to UV light, with increased predisposition to cancer (for XP and combined XP/CS, mostly), mental retardation and progeria (for CS and combined XP/CS). Whether the correlation between defective DNA repair reactions and UV-sensitivity/cancer may be more intuitive, a link with neurological/progeroid symptoms is still a matter of debate. As a possible explanation, it has been proposed a connection between NER and transcription regulation. We propose additional insights on XPG and XPC roles in transcription regulation in absence of exogenous stress and how CSA and CSB orchestrate transcription arrest due to genotoxic attack. XPC was able to stably interact with NSD3 methyltransferase. Mutations in XPC also disturbed the transcriptome and the H3K36me3 distribution. Mutations in XPG deregulate gene expression and XPG is able to be recruited genome wide together with TFIIH. CSA and CSB can, as part of the ubiquitin/proteasome machinery, regulate the recruitment timing of DNA binding factors and control transcriptional program after UV irradiation. Hence, our data shed more light in NER factors role in transcription and their defective action as a cause of XP and XP/CS disorders. Additionally, our data provide explanations on the mechanism of transcription arrest following genotoxic stress and pose questions about the origins of CS phenotype
15
Grossman, Sharon R. (Sharon Rachel). "Combinatorial gene regulation by transcription factors". Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/128406.
Testo completoAbstract (sommario):
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2019Cataloged from PDF of thesis. "The Table of Contents does not accurately represent the page numbering"--Disclaimer page.
Includes bibliographical references.
Combinatorial gene regulation is encoded in enhancers and promoters in the form of binding sites for transcription factors (TFs), which collaboratively recruit the transcriptional machinery and drive gene expression. Using high-throughput and quantitative technologies developed by our lab and others, we studied TF binding sites in enhancers from numerous different cell types and regulatory systems, shedding light general principles of motif composition and organization in typical cellular regulatory elements. We find extensive synergy between TF binding sites, some with organizational constraints and some with flexible positioning. We demonstrate that different TFs bind at distinct positions within regulatory elements, suggesting a new type of architectural constraint in enhancers. Importantly, our analysis of both TF organization and cooperativity revealed distinctive patterns that separates TFs into potential functional classes. Together, our results suggest a structure of the regulatory code at the level of TF function and generate new hypotheses about regiospecific binding patterns and functions of TF classes within enhancers.
by Sharon R. Grossman.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Biology
16
Montelius, Andreas. "Role of transcription factors in sensory neuron specification /". Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-115-9/.
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Jadlowsky, Julie Kendal. "Dual control of HIV transcription elongation virus-specific negative control by NELF-E is counterbalanced by positive transcription factor P-TEFb /". Cleveland, Ohio : Case Western Reserve University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1228234927.
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18
Cusack, Martin. "The role of DNA methylation on transcription factor occupancy and transcriptional activity". Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:7d0b7fe7-dee1-433f-8656-c9ee2a216d48.
Testo completoAbstract (sommario):
DNA methylation is an epigenetic mark that is deposited throughout the genome of mammals and plays an important role in the maintenance of transcriptionally repressive states across cell divisions. There are two major mechanisms by which DNA methylation has been proposed to act: one involves the recognition of the mark by protein complexes containing histone deacetylases (HDACs) that can remodel the local chromatin. Alternatively, methylation has been suggested to directly affect the interaction between transcription factors and their cognate binding sequence. The aim of this research was to determine the contributions of these two mechanisms in cells. The importance of HDAC activity in mediating DNA methylation-dependent transcriptional repression was assessed by comparing the genes and retrotransposons that are upregulated in response to DNA methylation loss or the disruption of HDAC activity. To this purpose, we performed whole-genome transcriptional analysis in wild type and DNA methylation-deficient mouse embryonic stem cells (DNMT.TKO mESCs) in the presence and absence of the HDAC inhibitor trichostatin A. Our data suggests that there are few genes whose repression is solely dependent on the recruitment of HDACs by DNA methylation in mESCs. Rather it appears that DNA methylation and HDAC-mediated silencing represent two independent layers of repression that converge at certain transcriptional elements. To investigate the contribution of DNA methylation on the genome-wide occupancy of transcription factors, we compared the global chromatin accessibility landscape and the binding profile of candidate transcription factors in the absence or presence of DNA methylation. We found that loss of DNA methylation associates with localised gains in accessibility, some of which can be linked to the novel binding of transcription factors such as GABPA, MAX, NRF1 and YY1. Altogether, our results present new insights into the interplay between DNA methylation and histone deacetylation and their impact on the localisation of transcription factors from different families.
19
Li, Yuxin. "The DEC1 transcription factor : oncogenic involvement and molecular mechanisms on transcription regulation /". View online ; access limited to URI, 2003. http://0-wwwlib.umi.com.helin.uri.edu/dissertations/dlnow/3115632.
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Eustis, Robyn Lynn. "The Role of Pyrococcus furiosus Transcription Factor E in Transcription Iniitiation". PDXScholar, 2015. https://pdxscholar.library.pdx.edu/open_access_etds/2522.
Testo completoAbstract (sommario):
All sequenced archaeal genomes encode a general transcription factor, TFE, which is highly conserved and homologous to the alpha subunit of the eukaryotic transcription factor TFIIE. TFE functions to increase promoter opening efficiency during transcription initiation, although the mechanism for this is unclear. The N-terminus of TFE contains a common DNA binding motif, a winged helix. At the tip of this winged helix is a highly conserved region of aromatic amino acids that is close to DNA during initiation. TFE activation can compensate for mutations in another transcription factor, TFB2, which is homologous to TFIIB. P. furiosus encodes two paralogs of the eukaryotic RNA polymerase II transcription factor TFIIB: TFB1 and TFB2. TFB2 lacks a portion of the highly conserved N-terminus, and functions in transcription complexes at a lower efficiency than TFB1. It has been demonstrated that the presence of TFE is able to assist in transcription with TFB2 in vitro bringing its efficiency to almost TFB1 levels. Thus, TFB2 provides a unique opportunity to evaluate the function of the TFE winged helix in transcription. In this study the aromatic patch of the TFE winged helix was mutated to test its role in activation of TFB1 and TFB2-containing transcription complexes, because this aromatic patch is required for full TFE activity especially when NTP concentrations are low.
21
SICILIANO, DILETTA. "ANALYSIS OF THE TRANSCRIPTIONAL REGULATION OF MTORC1 ACTIVITY BY MIT/TFE TRANSCRIPTION FACTORS". Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/607642.
Testo completoAbstract (sommario):
The mechanistic Target Of Rapamycin Complex 1 (mTORC1) regulates cellular biosynthetic pathways in response to variations in nutrient availability. Activation of mTORC1 is mediated by Rag GTPases, that act as heterodimers and promote mTORC1 recruitment to the lysosome. Many studies have clarified the post-translational control of mTORC1, but little is known about its transcriptional regulation. Our study demonstrates that TFEB, TFE3 and MITF, members of the MiT/TFE family of transcription factors and master regulators of lysosomal and melanosomal biogenesis and autophagy, are nutrient-sensitive transcriptional activators of mTORC1 signaling. During starvation they induce the expression of the RagD gene and this enhances mTORC1 recruitment to the lysosome and its reactivation when nutrients become available. Thus, in periods of nutrient deprivation, this mechanism allows the cell to rapidly reactivate anabolic pathways and turn off catabolism when nutrient levels are restored. Furthermore this mechanism plays an important role in cancer growth. Up-regulation of the MiT/TFE genes in renal cell carcinoma and melanoma is associated to RagD-induced mTORC1 activation, causing cell hyperproliferation and cancer progression.
22
Ferguson, Laura A. "The insulin promoter". Thesis, Available from the University of Aberdeen Library and Historic Collections Digital Resources, 2008. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?application=DIGITOOL-3&owner=resourcediscovery&custom_att_2=simple_viewer&pid=25965.
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Bhattarai, Arati. "The orientation of the Pyrococcus furiosus transcription factor TFB2 in the transcription initiation complex". PDXScholar, 2014. https://pdxscholar.library.pdx.edu/open_access_etds/1938.
Testo completoAbstract (sommario):
The hyperthermophile archaeon, Pyrococcus furiosus encodes two eukaryotic TFIIB family proteins, TFB1 and TFB2. TFB1 is very similar to TFIIB in terms of sequence homology and function, whereas TFB2 is unusual as it is missing highly conserved sequences in its N-terminal domain that are present in TFIIB and TFB1. Despite this, TFB2 is effective in transcription process, albeit with lower efficiency compared to TFB1. Other archaea also contain multiple TFBs, but unlike Pyrococcus furiosus TFB2, these multiple TFBs have higher sequence homology to each other and have similar transcription efficiencies. Photochemical cross-linking experiments have shown that the B-reader of TFB in archaea and TFIIB in eukaryotes is close to transcription start site and is very important in RNAP recruitment to promoter DNA and transcription start site selection. Thus the lack of the highly conserved B reader region in P. furiosus TFB2 presents the opportunity to further study the functional importance of this region.
In this study several amino acids in N-terminal domain of TFB2 were mutated with photoactivable unnatural amino acid p-benzoyl L- phenylalanine (pBpa) and the proximity of TFB2 relative to DNA was determined by photochemical cross-linking experiments. The results showed that TFB2 interacts with DNA near the TATA box via its C-terminal domain, and interacts with both strands of DNA near the transcription start site via its divergent B-reader and the B-linker sequences. The B-reader loop region is close to transcription start site and interacts with the transcribed strand of promoter DNA while the B-linker strand cross-links with the non-transcribed strand. Some of the amino acids in between the B-reader loop and the B-linker strand region in TFB2 are seen to cross-link both the transcribed and the non-transcribed strand. Thus, despite the absence of strong homology to conserved B-reader and B-linker sequences, TFB2 is likely to interact with DNA in the transcription bubble and facilitate in transcription initiation.
24
Tai, C. P. Andrew. "An in vivo analysis of specificity of gene transactivation by SOX proteins". Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B36906438.
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Tai, C. P. Andrew, e 戴賜鵬. "An in vivo analysis of specificity of gene transactivation by SOX proteins". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B36906438.
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Gueroult, bellone Marion. "Signatures nucléotidiques de l'activité des enhancers développementaux chez l'ascidie Ciona intestinalis". Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTS029.
Testo completoAbstract (sommario):
Les enhancers sont des régulateurs cruciaux de l’expression des gènes pendant le développement embryonnaire. L’ascidie Ciona intestinalis est un organisme-modèle qui se prête à l’étude de ces séquences cis-régulatrices car ses enhancers sont généralement petits et compacts, et le lignage invariant des cellules chez l’embryon permet de visualiser leur activité avec une résolution cellulaire. Deux signatures indépendantes associées à l’activité d’un enhancer avaient été identifiées : la présence de sites de fixation pour des facteurs de transcription spécifiques, et une signature dinucléotidique globale à l’échelle des enhancers. (Khoueiry 2010). Cependant, si ces signatures corrèlent avec l’activité des enhancers, elles ne permettent pas d’identifier de nouveaux enhancers grâce à leur séquence. Pendant ma thèse, j’ai utilisé un enhancer neural précoce de Ciona, le très bien caractérisé élément-a du gène Otx, comme enhancer-modèle. Ce petit enhancer (55pb), est lié par les facteurs de transcription GATA-a et ETS1/2 et activé par la voie de signalisation FGF. Afin de mieux comprendre les déterminants de l’activité neurale précoce d’un enhancer, j’ai testé l’impact de mutations ponctuelles affectant l’affinité de sites de fixation de l’élément-a pour les facteurs de transcription. J’ai également randomisé les séquences intercalantes, situées entre les sites de fixation pour ETS et GATA dans quatre clusters de ces sites.Nos résultats suggèrent au moins deux niveaux de contrôle de la régulation en cis : i) la spécificité spatiotemporelle de l’activité d’un enhancer est définie par l’identité des sites de fixation des facteurs de transcription, et ii) son niveau d’activité dépend à la fois de l’affinité des facteurs de transcription pour leurs sites de fixation et la composition des séquences intercalantes. La majorité des variants randomisés de l’élément-a sont actifs dans les mêmes lignées cellulaires que le sauvage et leurs niveaux d’activité sont très divers. Le même résultat est obtenu en randomisant les séquences intercalantes d’un autre cluster ETS/GATA actif. La randomisation de ces séquences a même conféré de l’activité enhancer à de nombreux variants de clusters inactifs. En accord avec leur activité neurale précoce et la présence de sites de fixations pour ETS et GATA, ces variants, comme l’élément-a, répondent à l’induction neurale de FGF. Nous n’avons pas réussi à expliquer l’action des séquences intercalantes sur l’activité des enhancers par des caractéristiques simples de leurs séquences (nucléotidique ou dinucléotidique), et l’on ne comprend pas pourquoi il est si simple de créer un enhancer synthétique quand la majorité des clusters génomiques de sites de fixations putatifs pour ETS et GATA sont inactifs. En utilisant une approche de fixation in vitro des facteurs de transcription, nous avons montré que la randomisation des séquences intercalantes peut affecter la fixation d’un facteur de transcription sur l’élément a, sans changer la séquence primaire du site de fixation, mais que la fixation sur l'élément entier ne peut pas toujours être expliquée par la fixation sur les sites isolées. Ces résultats suggèrent que la structure physique de l’hélice d’ADN autour des sites de fixation peut jouer un rôle important dans le contrôle de l’activité d’un gèneEnhancers are crucial elements for the control of gene expression during embryonic development. The ascidian Ciona intestinalis offers unique experimental features to study these cis-regulatory sequences: enhancers are generally small and compact and their activity can be tracked at the single cell level thanks to the invariant cell lineage of ascidian embryos.Previous work identified two independent signatures associated with enhancer activity: the presence of specific transcription factors binding sites (TFBS) and a global dinucleotide signature along enhancers (Khoueiry, 2010). Although they correlate with enhancer activity, these signatures are insufficient to identify enhancer sequences from their sole sequence. During my thesis, I used a well-characterized early neural Ciona enhancer, the a-element of the Otx gene, as a model enhancer. This small (55pb) enhancer, is bound by GATA-a and ETS1/2 and is activated by the FGF pathway. To better understand the determinants of early neural enhancer activity, I tested the impact of point mutations affecting the affinity of the a-element TFBS for their binding TF and of the randomization of the spacer sequences that separate the TFBS in four ETS and GATA binding site clusters.Our results suggest at least two levels of cis-regulatory control: spatiotemporal specificity of enhancer activity is encoded in the identity of TF-binding sites, while the level of enhancer activity is set both by the affinity of TFs for their binding sites and by the composition of the spacer sequences. A surprisingly high number of variants of the a-element with randomized spacers are active, always in the same cell lineages as the WT. These variants, however, display a wide range of activity levels. This effect is also observed when the spacers in another active ETS/GATA cluster are randomized. Randomization of the spacers can even confer enhancer activity to a large fraction of inactive cluster variants. Consistent with their early neural activity and with the presence of ETS- and GATA-binding sites, these variants are, like the a-element, responsive to the FGF neural inducer.We could not link the action of the spacers on enhancer activity to any simple nucleotide or dinucleotide sequence features and it currently remains unclear why it is so easy to create a synthetic enhancer while most putative genomic ETS/GATA clusters are inactive. Using in vitro transcription factor binding assays, we showed that randomization of spacer sequences can affect TF binding to the a-element without changing the primary sequence of the binding site, and that extended minimal TFBS do not always recapitulate binding to the whole element. These results suggest that the physical structure of the DNA helix around the binding sites may play an important role in the control of enhancer activity
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Castro-Mondragon, Jaime. "Development of bioinformatics methods for the analysis of large collections of transcription factor binding motifs : positional motif enrichment and motif clustering". Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0171.
Testo completoAbstract (sommario):
Les facteurs transcriptionnels (TF) sont des protéines qui contrôlent l'expression des gènes. Leurs motifs de liaison (TFBM, également appelés motifs) sont généralement représentés sous forme de matrices de scores spécifiques de positions (PSSM). L'analyse de motifs est utilisée en routine afin de découvrir des facteurs candidats pour la régulation d'un jeu de séquences d'intérêt. L'avénement des méthodes à haut débit a permis de détecter des centaines de motifs, qui sont disponibles dans des bases de données. Durant ma thèse, j'ai développé deux nouvelles méthodes et implémenté des outils logiciels pour le traitement de collections massives de motifs: matrix-clustering regroupe les motifs par similarité; position-scan détecte les motifs présentant des préférences de position relativement à une coordonnée de référence. Les méthodes que j'ai développées ont été évaluées sur base de cas d'études, et utilisées pour extraire de l'information interprétable à partir de différents jeux de données de Drosophila melanogaster et Homo sapiens. Les résultats démontrent la pertinence de ces méthodes pour l'analyse de données à haut débit, et l'intérêt de les intégrer dans des pipelines d'analyse de motifsTranscription Factors (TFs) are DNA-binding proteins that control gene expression. TF binding motifs (TFBMs, simply called “motifs”) are usually represented as Position Specific Scoring Matrices (PSSMs), which can be visualized as sequence logos. The advent of high-throughput methods has allowed the detection of thousands of motifs which are usually stored in databases. In this work I developed two novel methods and implemented software tools to handle large collection of motifs in order to extract interpretable information from high-throughput data: (i) matrix-clustering regroups motifs by similarity and offers a dynamic interface; (2) position-scan detects TFBMs with positional preferences relative to a given reference location (e.g. ChIP-seq peaks, transcription start sites). The methods I developed have been evaluated based on control cases, and applied to extract meaningful information from different datasets from Drosophila melanogaster and Homo sapiens. The results show that these methods enable to analyse motifs in high-throughput datasets, and can be integrated in motif analysis workflows
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Koo, Sonya Janet. "Downstream targets of motor neuron transcription factors /". Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2005. http://wwwlib.umi.com/cr/ucsd/fullcit?p3190171.
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Kinyanjui, Margaret. "Targeting Th2 transcription factors in experimental asthma". Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=18717.
Testo completoAbstract (sommario):
Antigen specific CD4+ T cells adoptively transfer airway inflammation comprised mainly of lymphocytes and eosinophils. The ability of these transferred T cells to induce inflammation is dependent on the cytokines they express particularly Th2 cytokines. In order to better understand the mechanism by which adoptively transferred T cells induce airway inflammation, we chose to modulate the expression (GATA-3) and activity (STAT-6) of two key regulators of Th2 cytokine production. To modify expression of GATA-3, we used a bicistronic retroviral vector encoding GATA-3 and enhanced green fluorescent protein (EGFP). As a control, we used a retrovector encoding EGFP alone. By coupling in vitro antigen stimulation with retroviral transduction we generated antigen specific CD4+ T cells expressing EGFP alone or GATA-3 and EGFP. When transferred into naïve recipients that were subsequently challenged, these transduced CD4+ T cells induced lung inflammatory responses with an increase in both CD4+ lymphocytes and eosinophils. This antigen specific inflammatory response was enhanced in animals receiving T cells overexpressing GATA-3. Analysis of the infiltrating cells also revealed that the EGFP+ T cells were present in the lung following antigen challenge, comprising only a small fraction of the CD4+ T cells recruited to the lung during the antigen response. Thus, GATA-3 amplifies antigen-specific inflammatory responses in the airways by augmenting the ability of antigen specific T cells to recruit inflammatory cells to the lung following antigen challenge. To modify the activity of STAT-6 we used chimeric cell penetrating peptides containing a poly-arginine protein transduction domain (PTD) coupled to a sequence predicted to bind and inhibit STAT-6 activity (SIP-1). Using fluorescein-tagged SIP-1, we demonstrate that the poly-arginine PTD efficiently translocates to the cytoplasm within an hour. In vitro, antigen-induced IL-4 production was inhibited in SIP-1-treated splenoLes cellules CD4+ T à antigènes spécifiques transfèrent par adoption l'inflammation pulmonaire constituées principalement de lymphocytes et d'éosinophiles. L'habileté de celles-ci à transférer des cellules T pour induire l'inflammation est dépendante de leur expression de cytokines Th2. De manière à mieux comprendre le mécanisme par lequel les cellules T transmises par adoption induisent l'inflammation pulmonaire, nous avons choisi de moduler l'expression de GATA-3) ou l'activité de (STAT-6) des deux régulateurs-clés de production de cytokine Th2. Afin de modifier l'expression de GATA-3 dans les cellules T destinées au transfert par adoption, nous avons utilisé un rétrovirus recombinant concentré avec une filtration par centrifugeuse. Ce procédé a dramatiquement augmenté leurs titres et ainsi leur habileté à transduire les cellules CD4+ T en culture primaire. Nous avons utilisé un rétrovirus recombinant qui encode la GATA-3 et / ou la protéine fluorescente verte (EGFP). En couplant in vitro la stimulation d'antigènes avec la transduction par vecteur viral, nous avons généré des cellules CD4+ T à antigènes spécifiques exprimant de l'EGFP seul ou bien de la GATA-3 et de l'EGFP. Lorsque transféré dans un rat qui avait subséquemment été provoqué avec des antigènes, ces cellules CD4+ T induisent une réaction aux inflammations pulmonaires avec une augmentation des lymphocytes et éosinophiles. Cette réaction inflammatoire fut accrue chez les animaux recevant les cellules T surexprimant la GATA-3. L'analyse des cellules infiltrantes a aussi révélé que bien que les cellules EGFP+ étaient présentes dans les poumons suivant la provocation par antigènes, elles étaient constituées seulement d'une petite fraction de cellules CD4+ T recrutées dans les poumons. Ainsi, la GATA-3 amplifie la réaction inflammatoire des poumons induite par antigènes en augmentant l'habileté des cellules T à antigènes spécifiques à recruter
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Ali, Asif. "Transcription factors in parathyroid development and embryology". Thesis, Open University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489906.
Testo completoAbstract (sommario):
The roles of two transcription factors, GATA3 and PARAFIBROMIN, that are involved in parathyroid function have been studied. Thus, loss of function mutations of the dual zinc finger transcription factor GATA3 result in hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome; whilst loss of function mutations of PARAFIBROMIN which is a nuclear protein with a likely role in the RNA polymerase complex, lead to the hyperparathyroidism-jaw tumour (HPT-JT) syndrome.
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Young, Neville Jonathan. "The role of transcription factors in odontogenesis". Thesis, King's College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393692.
Testo completo
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Friedrich, Dhana. "Oscillatory transcription factors and stochastic gene expression". Doctoral thesis, Humboldt-Universität zu Berlin, 2020. http://dx.doi.org/10.18452/22053.
Testo completoAbstract (sommario):
Transkriptionsfaktoren (TFs) empfangen Signale in Signaltransduktionskaskaden und übersetzen diese in eine zelluläre Antwort. Dadurch ermöglichen sie es Zellen, Organen und Organismen sich an verändernde Umgebungsbedingungen anzupassen. In früheren Studien wurde gezeigt, dass viele TFs nach Aktivierung Oszillationen im Zellkern aufweisen. Ein Beispiel dafür ist p53. Als zentrales Protein im Rahmen der zellulären Stressantwort reguliert es nach DNA Schaden die Expression hunderter Zielgene die das Zellschicksal steuern. Anomalien in der Aktivität von p53 stehen im Zusammenhang mit schwerwiegenden Erkrankungen wie der Krebsentstehung. Die Dynamik der Akkumulation von p53 im Zellkern ist abhängig von der Art des DNA Schadens und korreliert mit der resultierenden zellulären Antwort. Obwohl dieser Zusammenhang mehrfach gezeigt wurde, sind die zugrundeliegenden molekularen Mechanismen jedoch weitgehend unerforscht.
Mit der vorliegenden Arbeit soll ein Beitrag zum Verständnis dazu geleistet werden, wie p53 Oszillationen im Zellkern die Transkription von Zielgenen auf Einzelzellebene modulieren. Dazu wurden sieben Zielgene ausgewählt und mittels Einzelmolekül-Fluoreszenz in situ Hybridisierung und mathematischer Analyse charakterisiert. Es werden Ergebnisse der quantitativen, zeitaufgelösten mRNA Expression und der bursting Aktivität von Zielgenpromotoren mit Einzelzell- und Einzelmolekülauflösung dargestellt. Diese Analyse weist darauf hin, dass die Aktivierung von p53 nach DNA Doppelstrangbrüchen primär die Frequenz des stochastischen bursting der untersuchten Zielgene reguliert. Diese können anhand ihrer Promotoraktivität in drei Archetypen eingeteilt werden: anhaltend, transient und pulsierend, die jedoch nicht ausschließlich durch veränderte p53 Menge im Zellkern erklärt werden können. Stattdessen weisen die Ergebnisse darauf hin, dass Veränderungen im Acetylierungszustand der C-terminalen Lysinreste von p53 entscheidend für diese Gen-spezifische Regulation sind.Transcription factors (TFs) are receiver and compiler of cell signaling, transmitting incoming inputs into cellular responses that enable cells, organs and organisms to respond and adapt to a changing environment. In the past, it has been shown that many TFs exhibit oscillations of nuclear abundance over time when activated. One of these TFs is the tumor suppressor p53, a central hub in the signaling network regulating the cellular stress response, controlling cell fate decisions by changing the expression of hundreds of target genes. Aberrations in p53’s activity are related to severe human malignancies such as cancer. The dynamics of its nuclear accumulation are stimulus dependent and enable the p53 pathway to mediate distinct responses to cellular stress. However, the molecular mechanisms translating such dynamics to altered gene expression remain elusive. In this thesis, I analyzed how oscillations of p53 affect the transcriptional regulation of target genes in single-cells and at individual promoters. I chose a panel of seven targets and employed a combinatorial approach of single-molecule fluorescence in-situ hybridization and mathematical analysis. I present quantitative, time-resolved measurements of target gene mRNA expression and transcriptional bursting activity with single-cell and single-molecule resolution. The resulting data show characteristic principles how p53 nuclear accumulation increases transcriptional bursting upon stimulation and reveal gene-specific modulations. P53 target promoters are regulated by changing the fraction of active promoters, indicating burst frequency regulation. Based on this, genes can be grouped along three archetypes of promoter activity: sustained, transient and pulsatile. These archetypes cannot solely be explained by nuclear p53 levels or promoter binding of total p53. Instead, I provide evidence that the time-varying acetylation state of p53’s C-terminal lysine residues is critical for this gene-specific regulation.
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Gillis, William Joseph. "The evolution of metazoan GATA transcription factors /". Connect to title online (Scholars' Bank) Connect to title online (ProQuest), 2008. http://hdl.handle.net/1794/8568.
Testo completoAbstract (sommario):
Thesis (Ph. D.)--University of Oregon, 2008.Typescript. Includes vita and abstract. "This dissertation includes both ... previously published and unpublished co-authored material"--P. v. Includes bibliographical references (leaves 120-135). Also available online in Scholars' Bank; and in ProQuest, free to University of Oregon users.
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Gillis, William Joseph 1981. "The evolution of metazoan GATA transcription factors". Thesis, University of Oregon, 2008. http://hdl.handle.net/1794/8568.
Testo completoAbstract (sommario):
xiii, 135 p. ; ill. (some col.) A print copy of this title is available through the UO Libraries. Search the library catalog for the location and call number.This thesis explores the origin and evolution of animal germ layers via evolutionary-developmental analyses of the GATA family of transcription factors. GATA factors identified via a conserved dual zinc-finger domain direct early germ layer specification across a wide variety of animals. However, most of these developmental roles are characterized in invertebrate models, whose rapidly evolved sequences make it difficult to reconstruct evolutionary relationships. This study reconstructs the stepwise evolution of metazoan GATA transcription factors, defining homologous developmental roles based upon clear orthology assignments. We identified two GATA transcription factors ( PdGATA123 and PdGATA456 ) from the marine annelid Platynereis dumerilii to aid comparison of protostome and deuterostome GATA factors. Our phylogenetic analyses defined these as protostome orthologs of GATA1/2/3 and GATA4/5/6 vertebrate subfamilies, while the mRNA localization of the Platynereis GATAs showed ectodermal versus endomesodermal germ layer restrictions, similar to their vertebrate orthologs. To define the phylogenetic relationships of more divergent genes in the invertebrate models, we identified GATA homologs from recently sequenced protostome genomes. Molecular phylogenetic analyses, comparisons of intron/exon structure, and conserved synteny confirm all protostome GATA transcription factor genes are members of either the GATA123 or GATA456 class. These data allowed us to identify multiple protostome-specific duplications of GATA456 homologs and reconstruct the origin and relationships of all arthropod GATA genes. To probe GATA transcription factor evolution in deuterostomes, including vertebrates, we identified GATA factors in basal deuterostomes, including the cephalochordate Branchiostoma floridae and the hemichordate Saccoglossus kowalevskii. Phylogenetic analyses of these data independently confirmed that the ancestral deuterostome and chordate--like the bilaterian ancestor--possessed only two GATA transcription factors. This work was facilitated by a bioinformatics platform we are developing to identify gene families from preassembled genomic sequence. We generated anti- PdGATA antibodies to further explore the role of Platynereis GATAs in germ layer formation. We identified multiple presumptive endomesodermal cells in which nuclear localization of PdGATA456 protein first occurs and utilized PdGATA456 protein localization to follow endomesodermal cell populations throughout development. These analyses represent some of the first cellular and molecular analyses of Platynereis germ layer formation. This dissertation includes both my previously published and unpublished co-authored material.
Adviser: Stephan Q. Schneider
35
Kiosses, Theodore. "DNA binding specificity and transcriptional regulation of Six4 : a myotonic dystrophy associated transcription factor". Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/3948.
Testo completoAbstract (sommario):
Attaining an understanding of the mechanisms underpinning development has been amongst the cardinal scientific challenges of our age. The transition from a single cell organism to the level of complexity evidenced in higher eukaryotes has been facilitated by the advent of intricate developmental networks involving a plethora of factors that synergise to allow for precise spatio-temporal expression of the proteins present in higher organisms. Development is often portrayed as a domino like cascade of events stemming from relatively uncomplicated origins that go on to branch out and form associations and interactions amongst multitudinous actors that will inexorably lead towards a higher state of order. Transcription factors occupy a central position within this tapestry of interactions. They regulate expression of the various required proteins and they provide the cues for the developmental events that will eventually shape an organism. These factors frequently remain unknown until some occurrence causes developmental processes to fail and inadvertently focus attention on the factors that facilitate development. Myotonic dystrophy is a useful paradigm of such a developmental dysfunction that has led to the discovery of a transcription factor integral to both muscle development and gonadogenesis in both Drosophila and higher eukaryotes.
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Roberts, Karen. "Regulation of melanocyte-specific transcription by the transcription factors BRN-2 and microphthalmia". Thesis, Institute of Cancer Research (University Of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286144.
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Jahangiri, Leila. "Combinatorial gene regulation by T-domain transcription factors". Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610328.
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Ferrara, Giovanni Antonio. "Studies of transcriptional regulation by the vitamin D3 receptor and cAMP-responsive transcription factors". Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=69734.
Testo completoAbstract (sommario):
Cells of complex organisms communicate with each other by sending molecular signals. These signals can be classified by their solubility properties. Hydrophilic signals, in the form of peptides or small hydrophilic molecules, interact with extracellular receptors located on the surface of target cells. Binding of ligand to its receptor leads to transduction of an intracellular signal via a second messenger. Lipophilic signals (steroids, vitamin D$ sb3$, thyroid hormone, and retinoids) traverse the plasma membrane and bind to specific intracellular proteins, known collectively as nuclear receptors, rendering them active. These ligand-receptor complexes then regulate the transcription of target genes. In this thesis, transcriptional regulation by two different systems has been studied. First, recent evidence suggests that expression of the parathyroid hormone-related peptide (PTHrP) gene is sensitive to elevated levels of cyclic adenosine monophosphate (cAMP). Second, vitamin D$ sb3$ is activated in the kidney by hydroxylation and functions by diffusing across the plasma membrane of target cells and binding the vitamin D$ sb3$ receptor (VDR). (Abstract shortened by UMI.)
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Immarigeon, Clément. "Role of mediator complex subunits in transcriptional regulation by GATA and FOG transcription factors during Drosophila development". Toulouse 3, 2014. http://thesesups.ups-tlse.fr/2654/.
Testo completoAbstract (sommario):
Un enjeu majeur en Biologie est de comprendre comment les milliers de gènes composant le génome sont contrôlés afin d'être exprimés dans les bonnes cellules au bon moment. Cette régulation a lieu en grande partie à l'étape de pré-initiation de la transcription. Ce processus résulte de l'action concertée de nombreuses protéines, dont le complexe Médiateur (MED, ~30 sous-unités protéiques ou SU, >1,5MDa) qui joue un rôle conservé dans la régulation de la transcription des gènes par l'ARN Polymérase II (PolII), de la levure à l'Homme. Ce complexe se lie simultanément à la PolII et aux facteurs de transcription spécifiques (FT). Les FT reconnaissent et se fixent à des séquences régulatrices d'ADN, et dirigent l'expression de leurs gènes-cibles au cours du développement. Le complexe MED, ubiquitaire dans les cellules eucaryotes, semble intégrer le " code des FT " spécifique à chaque cellule, et réguler en conséquence le recrutement et l'activité de la PolII au promoteur des gènes-cibles des FT. La drosophile est un organisme modèle fournissant des outils génétiques puissants pour répondre à des questions biologiques importantes in vivo, notamment concernant la transcription génique. Une famille de FT, les GATA, est impliquée dans des processus développementaux similaires chez les mammifères et la mouche. Ils activent et répriment la transcription, selon le gène considéré et la présence de certains cofacteurs comme les protéines FOG. Le travail présenté ici vise à comprendre comment les FT GATA utilisent le MED pour réguler la transcription de leurs gènes cibles, positivement et négativement. Au cours de ce travail, nous avons généré les premières lignées mutantes pour le gène Med1, et entrepris la caractérisation des fonctions de la SU Med1, connue pour être un cofacteur des FT GATA chez les vertébrés. Nous avons montré que certaines SU MED (dont Med1, 12, 13, 15 et 19) sont impliquées dans des processus dépendant des GATA, tels que l'hématopoïèse, la morphogénèse du notum et la formation des soies mécanosensorielles dorso-centrales. Les deux derniers dépendent du FT GATA Pannier (Pnr) qui, seul, active la transcription des gènes pro-neuraux ac-sc, ou la réprime en présence de son partenaire FOG U-shaped (Ush). Des analyses clonales in vivo ont révélé que Med1, Med15 et Med19, ainsi que Med12 et Med13 appartenant au module détachable CDK8, sont critiques pour l'activation d'ac-sc de façon cellulaire-autonome, suggérant un lien fonctionnel avec Pnr. De manière intéressante, CycC et Cdk8 du module CDK8 ne sont pas requises pour l'activation d'ac-sc, mais sont requises pour sa répression dans les cellules voisines, soulignant la diversité d'action des SU MED in vivo. Med19 interagit physiquement avec Pnr, et pourrait donc être le point d'ancrage par lequel Pnr recrute le MED pour activer la transcription. De plus, le facteur FOG Ush inhibe l'interaction Med19-Pnr en formant un hétérodimère Pnr-Ush. La compétition pour se fixer à Pnr entre Med19 (co-activateur) et Ush (co-répresseur) pourrait expliquer les actions antagonistes de Pnr sur ses gènes-cibles. Med19 est également requise pour la transactivation par un autre GATA : Serpent (Srp, cf. Gobert et al. 2010). Nous montrons ici que Med19 interagit également avec Srp, suggérant que Med19 pourrait être un cofacteur général des GATA, alors que Med1 ne semble pas avoir d'affinité pour les GATA chez la drosophile (contrairement à la SU Med1 chez les mammifères). Cela soulève des questions quant à la manière par laquelle les interactions entre FT et SU MED apparaissent, puis sont conservées, ou non, au cours l'évolution. Ces résultats mettent en lumière des interactions croisées entre Med19, GATA-Pnr et FOG-Ush qui permettent de comprendre mécanistiquement comment Pnr active et réprime la transcription. Ce travail représente une étape importante pour la compréhension de la façon dont les combinatoires de FT sont intégrées par le MED pour aboutir à une régulation fine de la transcriptionA major aim of today's research in Biology is to understand how the thousands of genes composing the genome are regulated in order to be expressed in the right cells at the right time. This regulation occurs in large part before gene transcription, at the pre-initiation step. This process results of the concerted action of many proteins, including the large Mediator complex (MED, ~30 protein subunits, >1. 5 MDa), which plays a conserved and crucial role in the regulation of protein-coding genes transcription by RNA polymerase II (PolII), from yeast to humans. This modular complex makes direct core contacts with PolII and general transcription factors, while some subunits can bind to DNA-bound specific transcription factors (TFs). TFs recognize and bind specific regulatory DNA sequences, and drive the tissue-specific expression of their target genes during development. The ubiquitously expressed MED is thought to integrate a cell-specific STF "code" to regulate PolII recruitment and activity at gene promoters. Drosophila melanogaster is a valuable animal model that provides many genetic tools - such as mutant strains and transgenic lines - to address important biological questions in vivo, such as how gene transcription is regulated. A family of TFs, the GATAs, is involved in diverse developmental processes in both Drosophila and vertebrates. They are both activator and repressor TFs, depending on the target gene and the available cofactors, such as Friend Of GATA (FOG) family proteins. The work presented here aimed to understand how GATA TFs use the MED to regulate their target genes both positively and negatively. During the course of this work we generated the first Drosophila mutants for Med1, and investigated the functions of this important subunit in vivo, known as a cofactor of GATAs in vertebrates. We identified a subset of Drosophila MED subunits (including Med1, 12, 13, 15, 19) which are required for proper GATA-dependent processes, such as haematopoiesis, notum morphogenesis and dorso-central (DC) mechanosensory bristle emergence. The last two processes depend on Pannier (Pnr), a GATA-type TF, which directly activates achaete-scute (ac-sc) proneural genes transcription singly, and represses it in presence of its FOG partner U-shaped (Ush). Clonal analysis in vivo showed that Med1, Med15 and Med19, along with Med12/13 subunits of the detachable "CDK8" module of the MED, are critical for ac-sc activation in a cell-autonomous manner, suggesting functional interactions with Pnr. Interestingly, CycC and Cdk8 subunits from CDK8 module are not involved in ac-sc activation, but are required to ensure ac-sc inhibition in surrounding cells, underscoring the diversity of MED subunits functions in vivo. Moreover, we show that Med19 binds physically to Pnr. Thus, Med19 might be the anchor point by which Pnr recruits the MED at Pnr-activated genes. Furthermore, the FOG factor U-shaped inhibits Med19-Pannier interaction by heterodimerizing with Pannier. Thus, the competition for Pnr binding between Med19 (coactivator) and Ush (corepressor) could be responsible for the antagonistic roles of Pnr on the transcription of its target genes. Interestingly, Med19 is also required for transactivation by another GATA factor: Serpent (Srp, cf. Gobert et al. , 2010). Here we show that Med19 also interacts physically with Srp, suggesting that Med19 could be a general cofactor of GATAs in drosophila. On the other hand, Med1 showed no affinity for Drosophila GATAs (contrary to vertebrate Med1), raising questions about the way MED-TF interactions are acquired and maintained, or not, during evolution. This work highlights the interplay between Med19, GATA-Pnr and FOG-Ush, allowing a mechanistic understanding of Pnr actions as both an activator and a repressor of gene transcription. This PhD thesis is an important step towards appreciating how combinatorial codes of TFs are integrated by the MED to regulate gene transcription during development
40
Ranish, Jeffrey A. "Mechanisms of transcription by RNA Polymerase II /". Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/5057.
Testo completo
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Yang, Shu, e 杨澍. "Co-evolution of transcription factors and their binding sites". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46339863.
Testo completo
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Vaidya, Harsh Jayeshkumar. "Investigation of transcriptional regulation of Foxn1 in fetal thymic epithelial progenitor cells". Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/21697.
Testo completoAbstract (sommario):
The thymus in mice and humans originates from the third pharyngeal pouch endoderm. This process is divided into early Foxn1-independent stages and later Foxn1-dependent stages. Foxn1 is indispensible for the differentiation of thymic epithelial progenitor cells (TEPCs) as the development of thymus in Foxn1 mutant mice is arrested around E12.5. The transcriptional changes associated with the developmental of the thymus are poorly understood. In particular, the transcriptional regulation of Foxn1 in the developing thymic rudiment has not been definitively identified. Recently, Pax1, Pax9, Tbx1, and E2Fs have been implicated in transcriptional regulation of Foxn1. However, with the exception of E2Fs, evidence regarding their direct involvement in regulating Foxn1 expression is missing. Therefore, the aims of this thesis were to study the transcriptional regulation of Foxn1 through identification of its regulatory regions and studying the transcriptional changes associated with the developing thymus. These aims were addressed through the use of chromatin-immunoprecipitation technique combined with next-generation sequencing and gene expression analyses of the developing TEPCs. The data presented in this thesis identified H3K4me3 and H3K27ac marked Foxn1 promoter and five H3K4me1 and H3K27ac marked putative enhancer regions. The combination of gene expression analyses and transcription factor binding sites within the above regions suggested Ets1, Isl1, Foxc1, Nfia, Nfib, Srf, Foxo1, Nfatc2, Ing4, Foxa2, Hes1, E2Fs, and p53 as candidate transcriptional regulators of Foxn1. Nfatc2 appears also to be a target of Foxn1 that could play an important role in thymus development by regulating a large set of genes. Comparison of wild type and Foxn1 null thymus showed that Foxn1 could act as positive regulator of Pax1 and negative regulator of Gata3 and Eya1, genes important for third pharyngeal pouch development. The comparison of transcriptome of E10.5 and E11.5 third pharyngeal pouch cells and E12.5 TEPCs showed that genes involved in tissue development are downregulated while those involved in antigen presentation, a process important for thymus function, are upregulated during development. These results also demonstrated a decrease in the activity of transcription factor network involving Hox genes and an increase in the activity of a network involving Nfkb, Rela, and Irf genes. Analysis of signalling pathways suggested that the NFκB signalling pathway could be important for thymus development after E12.5 while TGFβ signalling pathway appeared to be detrimental to Foxn1 expression in thymic epithelial cells. Together, I identified several transcription factors that could be involved in transcriptional regulation of Foxn1 in TEPCs, several genes that could be a target of FOXN1, changes in transcription factor network and signalling pathways associated with the developing thymic rudiment.
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Sites, Emily. "Proposed Roles for Sox Transcription Factors and Growth Factor Receptors in NF1". University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1226071241.
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Sheffield, Kimberly Kay. "Interplay of Transcription Factor E and Spt4/5 During Transcription Initiation in Pyrococcus furiosus". PDXScholar, 2018. https://pdxscholar.library.pdx.edu/open_access_etds/4444.
Testo completoAbstract (sommario):
Transcription, the first step in gene expression, is a highly regulated process which relies on a multi-protein complex to occur. Among these proteins are transcription factors, including initiation and elongation factors, which play differing roles in early and late stages of transcription. The mechanisms of transition from transcription initiation to elongation are not well understood in archaea, nor are the structures of the transcription factors involved. For transcription to occur in vitro, transcription factors TATA binding protein (TBP) and Transcription Factor B (TFB) are sufficient to allow RNA polymerase (RNAP) to synthesize RNA from template DNA. Another factor, Transcription Factor E (TFE), can also join the initiation complex and is likely to be essential in vivo. TFE is known to contribute to initiation by enhancing promoter opening, and while it has been shown to persist in elongation complexes, its role after initiation is unknown. Spt4/5, the archaeal homolog of the only universally conserved RNAP-associated factor, is known to join complexes in elongation steps and enhance processivity of the polymerase. However, if Spt4/5 joins pre-initiated complexes, it has been shown to inhibit transcription activity. The experiments in this thesis show that TFE and Spt4/5 participate in a crucial interchange at the upstream fork of the transcription bubble that helps define the timing of Spt4/5 binding. Using unnatural amino acid crosslinking techniques, the points of proximity between specific regions of these two factors and the template DNA have been mapped to identify possible sites of interaction. Competitive crosslinking assays indicate the exact timing of the shift in affinity between TFE and Spt4/5 for their shared binding site on RNAP. These data, combined with transcription assays, suggest a new role for TFE in preventing premature Spt4/5 binding, corresponding with a unique localized mobility within the winged helix of TFE.
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何明孝 e Ming-how Ho. "Sequence variation and covariation in forkhead domains". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31970552.
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Ho, Ming-how. "Sequence variation and covariation in forkhead domains". Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25155283.
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Pang, Ting-kai Ronald. "Transcriptional regulation of the human secretin receptor gene /". Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25059324.
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Zhou, Shengli. "ZNF451 is a novel binding partner of the bHLH transcription factor E₁₂". Connect to full text in OhioLINK ETD Center, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=mco1225219996.
Testo completoAbstract (sommario):
Thesis (M.S.)--University of Toledo, 2008."In partial fulfillment of the requirements for the degree of Master of Science in Biomedical Sciences." Title from title page of PDF document. Bibliography: pages 49-62.
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Viart, Victoria. "Etude de la régulation transcriptionnelle et post-transcriptionnelle du gène CFTR : identification de facteurs de transcription et de microARNs". Thesis, Montpellier 1, 2011. http://www.theses.fr/2011MON1T031/document.
Testo completoAbstract (sommario):
Le gène CFTR, impliqué lorsqu'il est muté dans la mucoviscidose, est finement régulé au niveau tissulaire (principalement exprimé dans les organes cibles de la mucoviscidose) et au cours du développement. Par exemple, dans les tissus pulmonaires, l'expression du gène CFTR est plus forte chez le fœtus que chez l'adulte (75:1), où seulement deux copies en moyenne par cellule sont détectées.L'objectif de ce travail était de déterminer les mécanismes moléculaires responsables de cette régulation. Nous avons identifié de nombreux motifs cis-régulateurs au niveau de la région promotrice et de la région 3'UTR. Nous avons également caractérisé des facteurs de transcription, dont certains présentent une spécificité tissulaire et développementale. C'est notamment le cas des protéines de la famille FOX, des régulateurs clés dans le développement du système reproducteur et pulmonaire. Cette étude a également permis d'identifier le rôle de certains microARNs dans la déstabilisation des transcrits CFTR. Finalement, nous proposons un rôle combiné de ces différents acteurs dans la régulation transcriptionnelle et post-transcriptionnelle du gène CFTR. L'identification des éléments répresseurs devrait fournir de nouvelles cibles thérapeutiques pour la mucoviscidoseCFTR gene, involved in cystic fibrosis, displays a tightly regulated spatio-temporal pattern of expression (mainly expressed in taget tissues of cystic fibrosis). In lung, CFTR transcripts are abundant during fetal development compared to the adult stage (75:1), where only two copies per cell are detected. The aim of this work was to determine the molecular mechanisms involved in this regulation. We have identified several cis-regulatory motifs in the 5'UTR and the 3'UTR parts. We have characterized transcription factors with tissue- and temporal-specific activity. Members of FOX family are crucial regulators in reproductive duct and lung formation. We have also identified microRNAs in destabilizing CFTR transcripts. Finally, we propose a coupling role of trans-acting regulators in the transcriptional and post-transcriptional regulation of the CFTR gene. Characterizing the repressors would help to identify novel therapeutic tools in cystic fibrosis
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Towers, Terri L. "Vitamin D3-mediated transcriptional repression : of the granulocyte-macrophage colony stimulating factor gene /". Access full-text from WCMC, 1998. http://proquest.umi.com/pqdweb?did=733066141&sid=3&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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